Hyperinflammatory Reprogramming Marks the Transition from MASH to HCC

Background & Aims Up to 40% of metabolic dysfunction-associated steatohepatitis (MASH)-associated hepatocellular carcinoma (HCC) occurs in the absence of cirrhosis. Yet the biological features that underlie non-cirrhotic MASH-to-HCC progression remain poorly understood. We sought to define the cellular and molecular programs associated with non-cirrhotic MASH-to-HCC progression. Methods We integrated histopathological and biochemical assessments, bulk and single-cell RNA sequencing, serum cytokine profiling, and multiplex immunohistochemistry in Gubra-Amylin-NASH diet-fed mice that remained HCC-naïve or developed non-cirrhotic HCC. Key findings were evaluated in an independent human cohort of non-cirrhotic MASH and MASH-HCC. Results Body composition metrics, fibrosis severity, histopathology and liver injury markers poorly distinguished HCC-progressors from non-progressors. In contrast, bulk transcriptomics identified prominent immune dysregulation in cancer-primed adjacent non-tumor liver. Single-cell RNA-sequencing revealed coordinated hyperinflammatory reprogramming characterized by loss of Trem2 + macrophages, expansion of Trem2 low pro-inflammatory macrophages, immature neutrophil accumulation, T helper 17 skewing and heightened activation of dendritic and endothelial cells. Cell-cell communication analysis identified IL-1 as the most altered signaling pathway in HCC-progressors (pathway distance=7.95, top-ranked), with myeloid-derived IL-1β signaling emerging as a dominant axis targeting endothelial and immune populations. Elevated circulating IL-6 (154.3 vs. 30.1 pg/ml, p =0.065) and TNF (25.2 vs. 16.0 pg/ml, p =0.062) in HCC-progressors support a systemic hyperinflammatory phenotype. Human non-cirrhotic MASH-HCC adjacent non-tumor tissues similarly exhibited increased IL1B expression (log 2 expression=4.21 vs. 4.03, p <0.01) and enrichment of IL-1β-responsive inflammatory programs. Conclusions Non-cirrhotic MASH-to-HCC progression is associated with coordinated hyperinflammatory reprogramming across immune and stromal compartments. Myeloid-derived IL-1β is a central signaling axis within the cancer-permissive MASH microenvironment, providing a potential basis for HCC risk stratification and preventive intervention.